Cadherins are a family of cell adhesion molecules involved in cell-cell contact. There are more than 30 cadherin molecules in the family which consists of subclasses with individual binding specificities. There are well studied classic cadherins such as epithelial (E) cadherin, neural (N) cadherin and placental (P) cadherin which play key roles in the development and maintenance of tissues such as the epithelium. The cadherin family has also been classified by their amino acid similarities, which separate the cadherins into two groups, type I and type II. Then there are tissue specific cadherins such as cadherin-6 (CDH6).
CDH6 was first cloned and characterized in 1995 (Shimoyama et al., Cancer Res. 1995: 55 (10)2206-2211). The CDH6 cDNA isolated by Shimoyama was 4315 nucleotides and coded for a cadherin protein of 790 amino acids and exhibited 97% homology with rat K-cadherin (Shimoyama, supra). CDH6 is a type II cadherin with five extracellular cadherin repeats, a transmembrane domain and a cytoplasmic domain. In probing for normal tissue expression, CDH6 was detected in brain, cerebellum and kidney, with weaker expression in the lung, pancreas and gastric mucosa. In the nervous system, CDH6 was found to demarcate the auditory and somatosensory systems (Inoue et al., Mol. Cell Neuro. 2008: (39) 95-104). It was demonstrated that CDH6 is expressed by a subset of retinal ganglion cells (RGCs) in the eye responsible for such vision qualities as brightness, direction of motion or edges (Osterhout et al., Neuron 2011: 71(4)632-639). In the CDH6 knockout mouse, the absence of CDH6 cause loss of axon targeting. The CDH6 mutant axons elongated properly and were appropriately guided to their targets, but then grew through and past their connections (Osterhout, supra). In another study, CDH6 knockout mice demonstrated defects in vocalization (Nakagawa et al., PLOS 2012: 7(11) e49233).
Turning to its expression in cancer, the CDH6 cDNA was cloned from a hepatocellular carcinoma cell line, which was an early indication it may be involved in this type of cancer (Shimoyama, supra). The early work found CDH6 expression in several hepatoma lines, but no expression in normal liver. In later work, a group analyzed 216 patients with renal cell carcinoma and found that CDH6 expression correlated with this type of cancer (Paul et al., J Urology 2004 (171): 97-101). Shimazui found that renal cell carcinoma patients who expressed CDH6 and lacked E-cadherin expression had a poor prognosis (Shimazui et al., Clin. Cancer Res. 1998 (4): 2419-2424). It was also discovered that CDH6 was a TGF-B target and plays a role in thyroid cancer (Sancisi et al., PLoS One 2013; 8(9): e75489). Lastly, CDH6 was shown to be a biomarker for ovarian cancer (Kobel et al., PLoS One 2008 5(12): e232).
Antibody drug conjugates (“ADCs”) have been used for the local delivery of cytotoxic agents in the treatment of cancer (see e.g., Lambert, Curr. Opinion In Pharmacology 5:543-549, 2005). ADCs allow targeted delivery of the drug moiety where maximum efficacy with minimal toxicity may be achieved. As more ADCs show promising clinical results, there is an increased need to develop new therapeutics for cancer therapy.